Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles
Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles
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DOI：
10.1186/1471-2350-10-51
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发表时间：
2009-06-06
影响因子：
--
通讯作者：
Mornet, Etienne
中科院分区：
文献类型：
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作者：
Fauvert, Delphine;Brun-Heath, Isabelle;Mornet, Etienne
背景资料：轻度低磷酸酶症（HPP）表型可能是由于ALPL基因突变表现出残留碱性磷酸酶活性或严重杂合突变表现出显性负效应。为了确定我们未能检测到第二个突变的原因，在轻度HPP患者进行测序，并进行一个单一的杂合突变，我们测试了可能的显性效应的35个突变进行这些patients.Methods：我们测试的突变位点定向诱变。我们还对患者和对照组的8个外显子和内含子ALPL基因多态性进行了基因分型，以检测是否存在复发性内含子轻度突变。我们发现，大多数测试的突变表现出显性负效应，这可能是轻度HPP表型的原因，并且对于至少一些患者，结论：轻度HPP的发生部分是由于重度和中度突变的复合杂合性所致，但也有很大一部分是由于杂合性突变的显性负效应所致。
Background: Mild hypophosphatasia (HPP) phenotype may result from ALPL gene mutations exhibiting residual alkaline phosphatase activity or from severe heterozygous mutations exhibiting a dominant negative effect. In order to determine the cause of our failure to detect a second mutation by sequencing in patients with mild HPP and carrying on a single heterozygous mutation, we tested the possible dominant effect of 35 mutations carried by these patients.Methods: We tested the mutations by site-directed mutagenesis. We also genotyped 8 exonic and intronic ALPL gene polymorphisms in the patients and in a control group in order to detect the possible existence of a recurrent intronic mild mutation.Results: We found that most of the tested mutations exhibit a dominant negative effect that may account for the mild HPP phenotype, and that for at least some of the patients, a second mutation in linkage disequilibrium with a particular haplotype could not be ruled out.Conclusion: Mild HPP results in part from compound heterozygosity for severe and moderate mutations, but also in a large part from heterozygous mutations with a dominant negative effect.